Vol. 295, Issue 2, 447-452, November 2000

Induction of Cyclooxygenase-2 in Rat Gastric Mucosa by Rebamipide, a Mucoprotective Agent¹

Wei-Hao Sun, Shingo Tsuji, Masahiko Tsujii, Edhi S. Gunawan, Naoki Kawai, Arata Kimura, Yoshimi Kakiuchi, Masakazu Yasumaru, Hideki Iijima, Yoshiko Okuda, Yutaka Sasaki, Masatsugu Hori and Sunao Kawano

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine (W.-H.S., S.T., M.T., E.S.G., N.K., A.K., Y.K., M.Y., H.I., Y.O., Y.S., M.H.), and Department of Clinical Laboratory Science, School of Allied Health Sciences, Osaka University Faculty of Medicine, Yamadaoka, Suita, Japan (S.K.)

Recent studies indicate an expression of mitogen-inducible cyclooxygenase (COX-2) in gastric mucosa. Rebamipide, a mucoprotective agent enhances prostaglandin (PG) synthesis. The present study was designed to clarify the mechanism for rebamipide-induced mucosal protection. Male Sprague-Dawley rats were administered 5, 15, or 50 mg/kg/day rebamipide for 14 days. The expression of constitutive cyclooxygenase (COX-1) and COX-2 in gastric mucosa was determined using Western blot analysis. Another series of rats was used to examine 1) the levels of PGE₂ in stomach with and without pretreatment with a COX-2 inhibitor; 2) the protective action of rebamipide against gastric damage caused by 0.6 N HCl; and 3) the effects of a COX-2 inhibitor on rebamipide-induced gastric mucosal protection. COX-2 expression was enhanced, whereas COX-1 expression did not change significantly in the gastric mucosa of rats after treatment with rebamipide. The gastric mucosal PGE₂ was higher in the rebamipide groups than in the vehicle-treated group. Rebamipide also suppressed gastric damage induced by HCl in a dose-dependent manner. A COX-2 inhibitor blocked the rebamipide-induced increase in mucosal PGE₂, and mucosal protection induced by rebamipide. The results indicate that rebamipide induces COX-2 expression, increases PGE₂ levels, and enhances gastric mucosal defense in a COX-2-dependent manner. Thus, COX-2 has an important role in the effects of rebamipide on gastric mucosal protection.